Methamphetamine (MA) is a Schedule II stimulant that has become a highly abused drug in the US. The National Institute on Drug Abuse (NIDA) has reported that about 0.3% of the population, (>730,000) has used methamphetamine, and that children as young as 12 were among those users. Although there are behavioral programs that report a measure of success in treating addicts, there are currently no medications approved for the treatment of MA addiction. Drugs such as methamphetamine bind to vesicular monoamine transporter 2 (VMAT2), also known as solute carrier family 18 member 2 (SLC18A2) and block the vesicular uptake of neurotransmitters. VMAT2 sequesters neurotransmitters into cytoplasmic vesicles following uptake by plasma membrane transporters on presynaptic nerve terminals. In addition, methamphetamine serves as a substrate for VMAT2 and plasma membrane transporters, substituting for the neurotransmitters, and causing their release from vesicular pools. The subsequent increase in synaptic neurotransmitter availability is the foundation for methamphetamine's psychostimulant effects.
VMAT2 is located presynaptically on intracellular storage vesicles and monoaminergic nerve terminals. VMAT2 has been cloned and is comprised of 515 amino acids putatively arranged in 12 interconnected helices. The tertiary structure is not known. VMAT2 facilitates uptake of dopamine (DA) into vesicles, where it is stored and later released to maintain physiological concentrations of DA in the synapse. Indeed, without this storage capacity, physiological DA demands cannot be met by intracellular synthesis alone. MA, a VMAT2 substrate, causes the release of DA from vesicles into the cytosol of presynaptic neurons. It then affects the further release of DA into the extracellular space by physiological neuronal firing or by reverse transport by the DA transporter (DAT). The result is an increase of DA in the synapse (Dwoskin L P and Crooks P A Biochemical Pharmacology 63, 89 (2002) and Sulzer D et al, J Neurosci 15, 4102 (1995); both of which are incorporated by reference herein). This increase is the foundation for methamphetamine's psychostimulant effects which may lead to methamphetamine addiction (Wimalasena K, Med Res Rev 31, 483-519 (2010); Zheng G et al, AAPS Journal 8, E682 (2006); and Vartak A P et al, J Med Chem 52, 7878 (2009); all of which are incorporated by reference herein).
Reserpine, an alkaloid that inhibits neurotransmitter uptake into vesicles by VMAT2, binds with high affinity but in an essentially irreversible fashion to a site that is closely associated with the uptake site. Although it has been used extensively as an antihypertensive agent, reserpine's irreversible binding properties make it less clinically attractive as a potential pharmacotherapy for treatment of symptoms associated with MA abuse. Other drugs such as tetrabenazine (TBZ) analogues bind with high affinity to a site on the VMAT2 that apparently differs from the reserpine binding site, and they are under scrutiny as potential medications for the treatment of symptoms associated with psychostimulant abuse.